1/12/2009 @ 5:45PM

IBM's Sharp New Focus

Proteins are giant jumbles of amino acids shaped like a tangle of curled ribbons and crimped strings. But they are jumbled and tangled just so. How they are built and shaped determines whether they can help digest a bite of steak au poivre or play a role in crippling a flu virus.

The beautiful, messy collection of proteins in our bodies are made from a mere 20 amino acids. Figuring out what intricate shape they take, or “seeing” their structures, however, is hard.

Now researchers at
IBM
think they may be able to do just that: In a paper published Monday in the Proceedings of the National Academy of Sciences, the scientists describe the results of a new magnetic resonance imaging (MRI) technique that could give biologists a glimpse of the tangles and crimps of proteins down to a resolution of four nanometers (or billionths of a meter). That’s 100 million times sharper than the best research machines currently available.

IBM does not have a new MRI machine yet. Instead, the researchers are revealing the latest results of a technique they’ve been working on for a decade. It could still use some refining, but researchers report that they trained their device on a tobacco mosaic virus; for the first time, they have been able to create an image of a native organic molecule in three dimensions.

“[Traditional] MRI is beautiful, but because the signal it is picking up is so small you can’t extend it to very small scales,” says Daniel Rugar, manager of Nanoscale Studies at IBM’s Almaden Research Center in San Jose, Calif. “But now we’ve been able to take a native biological sample and take an image of it.”

John Marohn, a chemistry professor at Cornell University who has been working on this technique since 1996 but did not work on the IBM paper, concedes that this so-called nano-MRI “hasn’t told you anything new about a sample you haven’t known about before, which is kind of is what microscopes are for.”

But, he says, there is no other available technique that could possibly do what Rugar’s work now suggests can be done. “This is the first time where you can really start to taste applications coming,” he says. “We will very soon be able to answer some real science questions.”

The most commonly used current tool to visualize protein folding gave scientists their first images of such molecular structure. Called X-ray crystallography, it was first used to determine the structure of myoglobin, an oxygen-carrying protein, in 1958 (and its discoverers received the Nobel Prize for their accomplishments just four years later).

This method produces detailed and useful images of those proteins that can be crystallized. There are thousands, though, that can’t, like the receptors in cell membranes that send and receive signals. These receptors, and the signals that cascade into the cell and trigger cell behaviors, are intensely studied but barely understood. They are also often implicated in diseases like cancer.

Rugar and his researchers, working in conjunction with Stanford University’s Center for Probing the Nanoscale, have developed a technique that, like traditional MRI, uses a magnetic field to create vibrations in the nuclei of hydrogen atoms (which are single protons) sprinkled among every organic molecule.

Traditional MRI uses a magnetic coil to induce vibrations and an antenna to listen to the signals, the protons’ resonance. In Rugar’s method, called magnetic resonance force microscopy, the subject–in this case the tobacco mosaic virus–is attached to an extremely thin cantilever, like a diving board for molecules.

The diving board and subject are positioned near a tiny magnetic tip that creates a strong magnetic field. That magnetic field causes the protons in the subject to vibrate and bounce the diving board. A laser interferometer measures the resonance of the diving board, providing information about the chemistry of the subject.

“Normal MRI takes trillions of protons to get one pixel,” says Rugar. “We can get a signal from just 100 protons.”

But success hinges on two key technical points. First, protons vibrate in a unique way when subjected to a very specific magnetic field strength. Second, the strength of the magnetic field surrounding the tip rapidly fades as the subject is moved away from the tip.

This means that at any moment only a four-nanometer-wide slice of the subject is perfectly positioned to vibrate and move the cantilever. Rugar calls this the “resonant slice,” and it is what provides the researchers their resolution. They move the sample in three dimensions, gathering data as another four-nanometer resonant slice activates the cantilever.

“We can make the protons do whatever dance we want them to do,” says Rugar. “We make them flip over and flip back, and that creates the vibrations we want to measure.”

After the device has made on the order of 8,000 measurements, the researchers have to do their own flip, this a mathematical one called deconvolution, to process the data and fit it into a three-dimensional shape.

And there’s the image. Rugar thinks the device needs to boost its resolution by a factor of five before it can provide useful information about proteins. Improving the magnetic tip, with a field strength that falls off even faster than that in the current device, could boost the technique as much as tenfold, he figures.

“That’s what gives us hope we can push it to the single atom limit,” Rugar says. “But it will be useful long before we get there.”